Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood and has often a chronic course persisting into adulthood.
Trang 1S T U D Y P R O T O C O L Open Access
Neurofeedback in children with attention-deficit/
multicenter study of a non-pharmacological
treatment approach
Martin Holtmann1*†, Benjamin Pniewski1†, Daniel Wachtlin2, Sonja Wörz3and Ute Strehl3
Abstract
Background: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood and has often a chronic course persisting into adulthood However, up to 30% of children treated with stimulants either fail to show an improvement or suffer adverse side effects, including decreased appetite, insomnia and irritability and there is no evidence of long term efficacy of stimulants for ADHD A series of studies has shown that neurofeedback is an effective additional or alternative treatment for children with ADHD, leading to e.g
significant and stable improvement in behavior, attention and IQ Significant treatment effects of neurofeedback have also been verified in meta-analyses Most of the trials, however, have been criticized for methodological difficulties, particularly lacking appropriate control conditions and number of patients included This randomized study examines the efficacy of slow cortical potentials (SCP) -neurofeedback, controlling unspecific effects of the setting by comparing two active treatment modalities
Methods/Design: A total of 144 patients with ADHD, older than six and younger than ten years, in some cases with additional pharmacological treatment, are included in this trial In five trial centres patients are treated either with SCP-feedback or electromyographic (EMG) -feedback in 25 sessions within 3 months A comprehensive test battery is conducted before and after treatment and at follow-up 6 month later, to assess core symptoms of ADHD, general psychopathology, attentional performance, comorbid symptoms, intelligence, quality of life and cortical arousal
Discussion: The efficacy of SCP-feedback training for children with ADHD is evaluated in this randomized
controlled study In addition to behavior ratings and psychometric tests neurophysiological parameters serve as dependent variables Further, the choice of EMG-biofeedback as an active control condition is debated
Trials registration: Current Controlled Trials ISRCTN76187185 Registered 5 February 2009
Keywords: Neurofeedback, SCP, Slow cortical potentials, ADHD, Attention-deficit/hyperactivity disorder,
Electromyogram, EMG biofeedback
* Correspondence: martin.holtmann@wkp-lwl.org
†Equal contributors
1
Hospital for Child and Adolescent Psychiatry, LWL University Hospital Hamm
of the Ruhr-University Bochum, Heithofer Allee 64, 59071 Hamm, Germany
Full list of author information is available at the end of the article
© 2014 Holtmann et al.; licensee BioMed Central Ltd This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
Trang 2Attention-deficit/hyperactivity disorder (ADHD) is the
most common neurobehavioral disorder of childhood with
an estimated prevalence of 3-5% in school-aged children
[1,2] Core symptoms include according to DSM-5
im-paired attention, excessive motor activity, and impulsivity
[3] The disorder often has a chronic course with 30-65%
of affected children displaying ADHD symptoms in
adult-hood [4] Numerous problems are associated with ADHD,
including poor social relationships, higher risk taking
be-havior, and a higher incidence of anxiety and depression
symptoms Stimulant medication, e.g methylphenidate,
represents the most commonly used intervention for
chil-dren with ADHD However, up to 30% of chilchil-dren treated
with stimulants either fail to show an improvement or
suffer adverse side effects, including decreased appetite,
insomnia and irritability as well there is no evidence of
long term efficacy of stimulants for ADHD [5,6] After
medication washout children experience considerable
loss of improvement [7] Kratochvil et al [8] reported
on the effectiveness and tolerability of long-term
ato-moxetine treatment During a period of 2 years, more
than 25% of young children with ADHD discontinued
the treatment because of lack of effectiveness
Neurofeedback (NF) as an additional or alternative
treatment is based on neurophysiological changes
char-acteristic of ADHD children [9-11] (for an overview, see
Becker & Holtmann, [12]; Holtmann & Stadler [13])
This intervention has gained promising empirical
sup-port in recent years Before the initial application of this
clinical study, pilot studies had been carried out in three
of the five participating centers (Frankfurt, Göttingen,
Tübingen) For a group of nearly 50 ADHD children,
significant improvement in behavior, attention and IQ
was observed after NF All changes were stable or even
improved at six month [14,15] and two year follow-up
[16] Preliminary results of a prospective randomized
pilot study in 34 ADHD children comparing NF and a
computerized cognitive training indicate that only NF
showed specific effects on impulse control [17] Also,
data of a study in children with ADHD comparing NF
with a computerized cognitive training found an
advan-tage of NF on behavioral and neurophysiological
param-eters (Gevensleben et al., 2007) This supports the data
of Heinrich et al [18] who provided first evidence for
specific neurophysiological effects of NF in children with
ADHD, evidenced in a normalization of the contingent
negative variation (CNV), an event-related correlate of
attentional resources In a controlled functional
mag-netic resonance imaging (fMRI) study, Lévesque et al
[19] demonstrated the capacity of NF to normalize key
neural substrates of selective attention in ADHD
Fur-ther, it has been demonstrated that NF can lead to
microstructural changes in white and gray matter [20]
Several meta-analyses have been published on the ef-fects of neurofeedback on ADHD symptoms A first meta-analysis examined 467 subjects from 10 prospect-ive, controlled neurofeedback trials [21] and showed medium to high effects for all three core domain of ADHD symptoms A second meta-analysis, using a more rigorous methodological approach [22] found a significant treatment effect of neurofeedback (ES = 0.59; 95% CL: 0.31-0.87) using ADHD scores from raters (often unblinded) close to the therapeutic setting Since blinded assessments were only available from four out of the eight included studies, the authors concluded that better evidence for effi-cacy from blinded assessments is required before neuro-feedback can be supported as treatment for ADHD core symptoms This need is addressed in the present study that applies assessments by a blinded clinical investigator In addition, there is still lack of evidence whether the observed effects are specific results of the neurofeedback treatment and are not triggered by unspecific effects
Many studies on neurofeedback in ADHD have been criticized for lacking appropriate controls and follow-up, failing to randomly allocate participants to treatment conditions, using poor diagnostic criteria, and employing subjective and unblinded outcome measures [13,23] In addition, they failed to take into account the influence of the training setting provided by extensive biofeedback These limitations inhibit the acceptance of neurofeedback within the psychiatric and psychological communities Therefore, the aim of this randomized, controlled trial with parallel groups is to examine the efficacy of neuro-feedback in comparison to a self-regulation training using
a peripheral physiological parameter, controlling for pos-sible unspecific positive effects of the training setting First, we hypothesize that neurofeedback will show a bene-ficial effect on the core symptoms of children with ADHD that is superior compared to the control condition Sec-ond, we anticipate that patients will be able to sustain clinical improvement following neurofeedback after having washed out pharmacotherapy Furthermore, we want to investigate the effect of NF on the degree of ill-ness, the attentional performance, comorbid symptoms, intelligence, quality of life and cortical arousal For the first time adverse events as well as severe adverse events will be assessed
Methods
Patricipants and recruitment
Participants are being recruited and treated in the five trial centers (LWL University-Hospital Hamm, Ruhr-University Bochum; Central Institute of Mental Health Mannheim; Institute of Medical Psychology and Behavioral Neurobiol-ogy, Eberhard-Karls-University Tübingen; Department of Child and Adolescent Psychiatry, University of Göttingen; and Department of Child and Adolescent Psychiatry and
Trang 3Psychotherapy, Goethe-University Frankfurt) as
outpa-tients from seven to under 10 years with an ADHD
diag-nosis (for all eligibility criteria see Table 1) The diagdiag-nosis
is being verified in a semi structured interview based on
the German adaptation of the Kiddie-Sads-Present and
Lifetime Version (K-SADS-PL [24]) by one of the main
in-vestigators Considering the sample size calculation, 144
subjects are enrolled in the clinical trial (72 subjects per
treatment group) The Interdisciplinary Center for Clinical
Trials (IZKS) of the University of Mainz is responsible
for monitoring the study and for project-, safety-, data
management and biostatistics The IZKS Mainz is
sup-ported by the grant “Clinical Trial Centers [Klinische
Studienzentren], no FK 01KN1103, IZKS Mainz” from
the Federal Ministry of Education and Research
Ethics and written consent
This study (ISRCTN76187185) was approved by all local
Ethics Committees according to the Declaration of
Helsinki Before entering the study patients are informed
about the study objectives, study design, and potential risks
by one of the main investigators and receive this
informa-tion in writing also Written consent is obtained from all
participants and their persons in charge of primary custody
In addition children sign an adequate informed consent
Interventions
Experimental group: feedback of slow cortical potentials
Interventions were conducted following protocols of
pre-vious controlled studies with positive neurofeedback
out-comes [25-28] (for an overview, see Gevensleben et al
[29]; Arns et al [30]]) Slow cortical potentials (SCPs) are
very slow changes in the EEG and belong to the family of
event related potentials They reflect the excitability of the
underlying cortical area While negative shifts mobilize
resources for the preparation of motor and cognitive answers to a stimulus, positive shifts reflect inhibition
of mobilization [15]
Participants randomly allocated to the experimental group receive 25 sessions of neurofeedback of SCPs, with each session lasting about 60 minutes This in-cludes time needed for electrode montage as well as four
10 minutes blocks of feedback Each block consists of 40 trials and each trial is composed of a baseline-phase (2 seconds) and a feedback-phase (8 seconds) The feed-back electrode is being placed at Cz and referenced against an electrode behind the left ear (mastoid) In addition one ground electrode is placed on the right mastoid and four electrodes around the eyes to enable
an online correction of artefacts produced by eye move-ments The training protocol prompts either negative potential or positive potential shifts compared to the baseline [15] If patients are successful for at least 2 sec-onds in total during the second half of the feedback-phase
a sun is shown as a positive reinforcement Negativation and positivation are trained in a randomized succession, within the first 12 training sessions in a 1:1 ratio Respect-ively the focus on negativation, the ratio is being changed
to 4:1 within the last 13 sessions
Participants are sitting in front of a computer screen and connected to a multichannel amplifier which re-cords EEG as well as EMG activity (NEURO PRAX®; neuroConn GmbH, Ilmenau, Germany) Using previous research as a basis the treatment is being administered two to three times a week, and feedback animations pro-vided are simple During each session feedback is given in block 1, 2 and 4 To enable transfer of self-regulation skills
to everyday life participants perform the third block of each session without continuous feedback (transfer trials) Between the 12th session and the 13th session a period of
Table 1 Eligibility criteria
Inclusion criteria Attention-deficit/hyperactivity disorder (combined type) (DSM-IV)
Being 7 to 9 years of age Ability to understand character and individual consequences of the trial Written informed consent of the person with primary custody must be available before enrolment in the trial Exclusion criteria Diagnosis of bipolar disorder, psychosis, serious OCD, chronic serious tics or Tourette syndrome
Major neurological or medical illness Pharmacotherapy for severe anxiety and mood disorders and psychosis Acute suicidal tendencies
IQ below 80 (CPM) Non-German speaking child and primary caretaker
No telephone Pregnancy and lactation Participation in other clinical trials and observation period of competing trials, respectively.
CPM Coloured Progressive Matrices, DSM-IV Diagnostic and Statistical Manual of Mental Disorders, version IV, OCD Obsessive Compulsive Disorder.
Trang 43 weeks without training sessions is being arranged.
During that period participants have to conduct short
transfer exercises where they use the strategies of
self-regulation at least three times a day Little memo-cards
that depict the monitor with a successful self-regulation
trial serve as a cue to remind the participants to
exer-cise the self-regulation In addition they receive a DVD
with a video showing trials with both tasks simulating
the situation in the lab to prompt self-regulation at
home To strengthen the transfer the last 10 sessions
are followed by a short transfer exercise as described
above before doing some homework in the lab
Partici-pants are able to earn a certain amount of tokens for
taking part and good cooperation These tokens are
honored by little presents or vouchers as soon as a
cer-tain amount is collected
Control group: feedback of electromyographic activity of
the musculi supraspinatus
To control the degree of researcher-participant interaction,
as well as other non-specific effects of the feedback-setting,
children assigned to the control group attend 25 sessions of
electromyography (EMG-) biofeedback The training
proto-col reinforces muscular contraction and relaxation of either
the left in relation to the right Musculus supraspinatus or
vice versa, compared to the baseline Two electrodes are
placed at the upper shoulder area (left and right)
Partici-pants of the control group are being instructed to move the
object on the screen by contracting and relaxing these
mus-cles Duration of sessions, amount of transfer trials, surface
of the feedback monitor, reinforcement schedules, electrode
montage and transfer exercises are identical in both groups
Both interventions are being administered in addition to
treatment as usual (TAU) TAU may comprise
pharmaco-therapy with psychostimulants (short or long acting), e.g
methylphenidate and amphetamine salts, and
atomoxe-tine, and medication for Oppositional Defiant Disorder
(ODD) and Conduct Disorder (CD), that are treated
pharmacologically similar to ADHD To assess the unique
effects of the interventions, their stability over time and
the need of further pharmacotherapy, medication is being
washed out before the pretest to establish an unmedicated
baseline and after the intervention phase in both groups
The duration of the washout is adapted to the type of
medication, with a 2-week period for psychostimulants
and 4 weeks for atomoxetine In cases of lacking
practic-ability a minimum washout period of 48 hours (for
psy-chostimulants) and/or 5 days (for atomoxetine) is allowed
and medication is administered again in case of relapse
The timeline of the study is shown in Figure 1
Randomization and blinding
After screening, patients are randomly assigned to either
the neurofeedback training (experimental group) or
electromyographic (EMG)-biofeedback training (control group) Randomization is stratified according to trial site and sex in a 1:1 ratio (neurofeedback vs EMG-biofeedback) Other prognostic factors are considered by means of adjusted analysis A web based randomization tool developed at IZKS Mainz is used within this trial Randomization lists generated at IZKS Mainz by means of
a SAS (Statistical Analysis System) program are imported into this tool For practical reasons, the primary investiga-tors of the study who deliver treatments (but are not in-volved in outcome ratings) are aware of the participants’ allocation, but all medical consultants are blinded to the allocation Also parents and participants are not being in-formed about the randomization outcome but from the start of the training sessions the latter are receiving in-structions dependent on the outcome All participants are connected with both peripheral (EMG) and scalp (EEG) electrodes Training devices and software are identical for both interventions
Assessments FBB-ADHS
The German ADHD Rating scale consists of 20 items that assess the severity and perceived burden of inattention, hyperactivity, and impulsiveness as defined by the ICD-10 and DSM-IV and has been used widely in treatment studies for ADHD [31] It can be used to directly compare effect sizes between different kinds of interventions The German version has shown good psychometric properties, with good internal consistency (α coefficient = 0.78 – 0.89) for parent-rating [32] and (α coefficient > 0.90) for teacher-rating, and good inter-rater reliability (r = 0.70) [33]
Clinical Global Impression Scale
Assessment of general psychopathology is being per-formed using the Clinical Global Impression Scale (CGI)
to estimate symptom severity (CGI-S) and improvement (CGI-I) [34,35] The CGI is a seven-point scale that re-quires a rating of illness severity at the time of assessment Because severity estimation in the CGI is performed in re-lation to other patients, it is a subjective assessment tool Ratings are performed by a medical consultant blinded to group allocation
Testbattery for Attentional Performance
The Testbattery for Attentional Performance (TAP) ex-amines a large spectrum of specific attentional perfor-mances in a computerized form [36] The following two subtests are being administered
1) Go/Nogo This subtest assesses the ability to suppress a response in the presence of irrelevant stimuli Omission errors, committed errors, average reaction time and intraindividual variance of
Trang 5reaction time are analyzed in both subtests to
estimate changes in the attention performance
2) Flexibility (non-verbal) This subtest assesses the ability
to shift the attentional focus, measuring reaction times
for valid and invalid cues in a visual task
The TAP is a well validated measurement with
satisfy-ing psychometric properties [36]
Neurophysiological parameters: a) quantitative EEG and
b) event related potentials
Two neurophysiological parameters are ascertained using
an EEG amplifier (19 electrodes, 10–20 system):
a) Quantitative EEG (QEEG) is recorded during
6 minutes resting condition (3 minutes eyes closed
and 3 minutes eyes open) and during the first, last
and follow-up training session, with the same
equipment used for feedback but at 19 electrodes
After correction for eye artefacts from the recording
channels power spectral analysis, displayed as a
topographical brainmap showing the absolute and
relative power for delta, theta, alpha and beta
frequency are analyzed
b) Event related potentials (ERPs) are recorded in a
cued Continuous Performance Task (CPT-OX [37])
The CPT-OX measures a person's sustained and selective attention and impulsivity By its embedded Go/Nogo task the CPT-OX captures a sequence of attentional and preparatory brain processes initiated
by the cue stimulus (indexed by Cue P300 and CNV) which precede inhibitory control (indexed by Nogo P300 (e.g [38]) The average reaction time, number of omission and commissions and mean amplitude of CNV and P300 is assessed Additionally Error-related negativity (ERN, a marker of action monitoring and error processing) is recorded in an Erikson flanker task (ERN-FT [39]) Average reaction time and number of errors for each condition (congruent/incongruent) is assessed
Child Behavior Checklist
The Child Behavior Checklist (CBCL) is one of the best-studied, empirically derived parent checklists for meas-uring general child and adolescent psychopathology [40] and is applied to assess comorbid symptoms The child’s behavior over the past 6 month using a total of
118 items (plus 2 optional questions) is rated by parents
or primary caregivers The questionnaire includes a total problem score, two superior scales (externalizing problems and internalizing problems), and eight syndrome scales (withdrawal, somatic complaints, anxiousness/depression,
Screening:
Diagnosis ADHD
Check inclusion criteria
Informed consent
4 weeks Medication washout 5 months
6 months Follow-up
3 months Treatment-phase Screening phase
Neurofeedback
25 sessions within 3 months under medication
EMG-Feedback
25 sessions within 3 months under medication
Post-Tests 2 minus Pretests
Main outcome: Specific Effects of Neurofeedback?
Follow-up Tests minus Post-Tests 2
Sustainability of effects?
2 - 4 weeks Medication washout
Figure 1 Flow chart.
Trang 6social problems, thought problems, attention problems,
delinquent behavior, and aggressive behavior) The
reli-ability, factorial validity and discriminant validity of the
German adaptation of the CBCL have been confirmed
by several studies [41,42] In case of comorbid
symp-toms (assessed by the individual syndrome scores)
add-itional corresponding parents’ rating scales of the
Diagnostic-System for Mental Disorders in Children
and Adolescents (DISYPS-KP [43]) are applied
Strengths and Difficulties Questionnaire
In addition to the CBCL, the Strengths and Difficulties
Questionnaire (SDQ) is used in order to assess
short-term changes of comorbid symptoms and evaluate
par-ent and teacher ratings The SDQ is a brief behavioral
screening questionnaire assessing 25 attributes, some
posi-tive and others negaposi-tive, which can be allocated to five
scales (emotional symptoms, conduct problems,
hyper-activity/inattention, peer relationship problems, and
pro-social behavior) [44] These scales can be summed to
calculate a total difficulties score with the advantage of
be-ing able to assess short-term changes [45] In this study
parent and teacher ratings with the SDQ are used The
sensitivity to change of SDQ allows estimation of
treat-ment efficacy (α = 0.73; retest stability = 0.62) [46] and
monitoring of symptom changes compared to screening
Coloured Progressive Matrices
Full scale intelligence quotient (IQ) is measured using the
Coloured Progressive Matrices (CPM) [47] The CPM is a
language-free intelligence screening test consisting of 36
items and standardized for children between 4 and 11 years
of age It provides a parallel version (Split-Half Reliability
of r = 0.85 to 0.90) to minimize test-retest-effects
(test-re-test coefficient r = 0.86 to 0.90)
Quality of life questionnaire
The revised German Kid-KINDL(R) quality of life 24 item
questionnaire is a reliable, valid and practicable
instru-ment [48] yielding six dimensions (body, psyche,
self-esteem, family, friends, and functional aspects) and a total
score The self-rating for children between 7 and 13 years
of age is applied to participants The internal consistency
for subscales reached values fromα = 0.54 to α = 0.73, with
anα = 0.82 for the total score [49]
Parents’ expectations on-/satisfaction with therapy
The expectations before treatment, and the satisfaction
with therapy during and after treatment is rated by parents
using a questionnaire that was developed by the Institute
of Medical Psychology and Behavioral Neurobiology,
Tübingen [50] The questionnaire consists of six questions
based on a 6-point Likert scale To avoid bias through
social expectancy parents submit the questionnaire dir-ectly to IZKS Mainz
Adverse events and serious adverse events
At each contact (assessment and training-session) partic-ipants are asked to report any adverse events (AEs) AEs are assessed by using open questions, asking about gen-eral AEs and their severity during the study period
Time points of assessments
The assessment time points are as follows
Screening: Eligibility criteria are examined in a first appointment
Pre-test: After washing out the medication as outlined above the initial assessment is carried out
to establish an unmedicated baseline
Post-test I: After 3 months of either neurofeedback
or EMG-biofeedback, there is a comprehensive post-therapy assessment
Post-test II: One month later, a second comprehensive post-therapy assessment is provided
To compare an unmedicated state to the baseline (established in the Pre-test) again medication is washed out before
Follow-up-test: Six months after the training-phase has ended, another comprehensive assessment is carried out Medication is washed out before
Additionally the parent version of the FBB-ADHS is assessed monthly An overview of the time points and the applied assessments is given in Table 2 All ques-tionnaires are presented in German, and are being com-pleted within the different treatment centers with exception of the teachers’ assessments (surface mail) and the monthly assessment of the FBB-ADHS after Post-test II (phone)
Primary and secondary endpoints
The primary endpoint of this study is the change in ADHD rating scale (FBB-ADHS) after treatment and washout of medication (Post-test II minus Pretest) Secondary endpoints include:
CGI-I
Resumption of medication by choice of family during follow-up
Change in neuropsychological and neurophysiological parameters
Change in SDQ questionnaire subscales
Change of full-scale IQ in CMP
Change in KINDL(R) questionnaire (both parents and child version)
Score measuring parents' satisfaction with therapy
Trang 7Pre-specification
A detailed methodology for summary and statistical
ana-lysis of the data collected in this trial is documented in a
Statistical Analysis Plan (SAP) that is dated and
main-tained by IZKS Mainz The document may modify the
plans outlined in the study protocol; however any major
modifications of the primary endpoint definition and/or
its analysis are also reflected in a protocol amendment
The SAP has to be authorized before database closure
by the biometrician and the coordinating investigator
Sample-size calculation
Estimates of a clinically relevant effect size were derived
from the Göttingen pilot-study using the same primary
outcome measures [18] It is expected that in the
neuro-feedback group the mean FBB-ADHS score at Post-Test
2 is 1.20 and in the control group 1.50 with a common
standard deviation of 0.55 The expected outcome
re-quires a sample size of 72 subjects per group (α = 0.05,
two sample t-test, two-sided) to achieve a power of 90%
Statistical analysis
Data are analyzed primarily in the modified
intention-to-treat (mITT) population Supportive analyses are planned
in the per-protocol (PP) population mITT comprises all
randomized patients with the exception of patients for
which it is obvious at the time of randomization that no
study specific therapy would be applied, while PP analysis assesses mITT patients who do not meet any of the fol-lowing criteria: violation of inclusion and/or exclusion cri-teria, major deviations from the visit schedule, and bad compliance during feedback sessions All safety parame-ters are analyzed in the safety population comprising all patients participating in at least one feedback session Within these analyses patients are analyzed according to the received treatment even if the respective patient was randomized to the other treatment group
In the primary analysis the primary outcome is tested by
an analysis of covariance (ANCOVA) using treatment, trial site, baseline FBB-ADHS score, baseline ADHD medica-tion, parenting style, parent’s expectations, and sex as co-variates The analysis is repeated for the PP population as
a sensitivity analysis In further analyses other potential predictors of response to treatment are examined Second-ary outcome measures comprise binSecond-ary variables and scores derived from standardized questionnaires For bin-ary variables proportions and relative risks together with their associated 95% confidence-intervals are calculated Differences between intervention groups are assessed using logistic regression models Scores are described
by distributional parameters (mean, standard deviation, median, quartiles, and range) In case the assumption of normally distributed data can not be rejected, differ-ences in the scores between intervention groups are an-alyzed by an ANCOVA using the same predictors as in
Table 2 Time points of assessments
Phase
Follow-up-test Action
Parents ’ expectations/
satisfaction
CBCL Child Behavior Checklist, CGI Clinical Global Impression Scale-Severity /Improvement, CPM Coloured Progressive Matrices /parallel version, EFB-K Erziehungsfragebogen (German version of the PS, Parenting Scale), ERPs Event related potentials, FBB-ADHS Fremdbeurteilungsbogen für Aufmerksamkeitsdefizit-/Hyperaktivitätsstörungen (German ADHD rating scale), Kid-KINDL(R) Revised German quality of life questionnaire, QEEG Quantitative EEG, SDQ Strengths and Difficulties Questionnaire, TAP Testbattery for Attentional Performance.
Trang 8the primary analysis In case of major deviations from
ANCOVA requirements, appropriate non-parametric
methods are applied
Quality assurance
Data management
A detailed methodology for the data management in this
trial is documented in a data management plan that is
dated and maintained by IZKS Mainz This plan is signed
by the sponsor, the head of the data management team and
the responsible data manager This trial is performed using
an electronic case report form (eCRF) or remote data entry
(RDE) The investigator and the trial site staff receive
sys-tem documentation, training and support for the use of the
eCRF During data entry integrity checks help to minimize
entry failures These data entry checks are based on the
data validation plan Any missing data or inconsistencies
are reported back to the respective site and clarified by the
responsible investigator After completion of data entry and
if no further corrections are to be made in the database, the
access rights are taken away and the database is declared
closed and used for statistical analysis
Monitoring
Monitoring is done by personal visits from a clinical
moni-tor according to prior defined standard operation
proce-dures of the IZKS Mainz By frequent communications
(letters, telephone, fax), the site monitor ensures that the
study is conducted according to the protocol and regulatory
requirements The investigator has to allow the monitor to
look at all essential documents and has to provide support
at all times to the monitor Furthermore, queries are
re-solved in cooperation with the investigator Close-out visits
are conducted to close the study site at the end of the study
and to ensure that all study-related documents archived
Advisory board
An independent advisory board is established This
ad-visory board is supposed to act as a data monitoring and
safety board during non-public meetings in the absence of
the principal investigator The advisory board supervises
the conduct of the study and issues recommendations for
early termination, modifications or continuation of the
study, if necessary It has to be informed contemporary of
serious study related events
Discussion
This paper presents the design and protocol of a
random-ized controlled trial (RCT) with neurofeedback for
chil-dren with ADHD in an outpatient setting The choice of
EMG biofeedback as a control condition was made after
an extensive discussion Although there is no doubt
that double-blind, placebo-controlled trials could provide
strong evidence for the efficacy and specificity of a given
treatment, there are several issues of a“sham” condition specially in neurofeedback Apart from the ethical issues, the feasibility of a sham condition for neurofeedback is doubtful Birbaumer et al [51] once tried to establish a double-blind sham condition in a neurofeedback trial for patients with epilepsy Patients as well as the trainer “de-tected” the sham sessions and refused further cooperation Furthermore neurofeedback in particular seems to induce the assumption that one is part of the placebo control In previous placebo-controlled trials of neurofeedback, up to 80% of the participants of the neurofeedback groups esti-mated (after treatment) that they received placebo feed-back [52,53] As we have learned from one of our pilot studies [15] it takes time until children are able to self-regulate their brain activity Therefore clinical improve-ment becomes evident only after a certain delay The impression of uncontrollability that arises especially in the beginning might assume that missing effects are due to the control condition and therefore may lead patients to discontinue participation Therefore, the present design made use of EMG biofeedback as an alternative control condition, based on the following considerations: There are not many studies on EMG Feedback available with satisfy-ing methods and/or results A review of 44 studies [54] concludes that the data do not suggest that biofeedback (i.e EMG) techniques are superior to more conventional treat-ment A detailed analysis of the studies included in this re-view leads to an even more pessimistic estimation of the effects Original work published after 1981 does not show much improvement No study reports follow-up data (e.g [55]), diagnosis is based on teachers’ ratings [56], some of the improvements are found in the placebo-group as well [57] and EMG Feedback was frequently carried out in addition to other treatments Arnold [58] concludes from his comprehensive review that EMG Feedback“merits fur-ther studies” Although not tightly connected to the known pathology of ADHD, relaxation of muscles can have effects
on the EEG [59] Therefore possible changes in the EEG are controlled by the QEEG (secondary measure) in this study As shown by Bakhshayesh et al [60] EMG Feedback does have an effect on core symptoms of ADHD albeit not
as much as EEG-Feedback Therefore from an ethical view-point EMG-Feedback is not just “empty” and senseless, possibly reflecting the desirable placebo effect of the treat-ment as being rewarded for being attentive, concentrated and cooperative Moreover it is to mention that a blinded setting might work well in drug research but seems an in-appropriate requirement in psychotherapeutic treatments where subjects are supposed to learn a certain behavior In Biofeedback the task is to acquire a self-regulation skill At least the first stage of this learning process requires con-scious control over the target variable [61] As observed by Surwit and Keefe [62] without knowing which parameter is being trained subjects are less effective in the acquisition of
Trang 9control This all amounts to the conclusion that the EMG
biofeedback applied in this design is an adequate, satisfying
and credible control condition If the trial supports the
ef-fectiveness of neurofeedback in reducing ADHD core
symptoms in the absence of stimulant therapy, this would
offer an effective alternative for those ADHD patients
whose treatment is up to now limited by poor medication
response, adverse side effects, and in cases in which the
pa-tients and/or their parents refuse medication treatment In
children who respond to pharmacotherapy, medication
could be withdrawn after successful neurofeedback training
Beyond the immediate research setting, neurofeedback
might be expanded to other behavioral disorders
The present study examines the effects of neurofeedback
on behavioral as well as neurophysiological parameters
comprising attentional, preparatory, time processing, and
inhibitory ERP components In a longitudinal study of
neuropsychological and electrophysiological markers of
different ERP components Doehnert et al [63] suggest
that especially preparatory and time processing brain
pro-cesses indexed by CNV remained detectable in young
adult ADHD subjects, even in ADHD remitters, compared
to controls The results seem to indicate residual timing
deficits even in young adults with remitted ADHD
Hein-rich et al [18] investigated the effects of a neurofeedback
training aiming at generating a ‘more negative’ CNV in
children with ADHD compared with a waiting-list group
Besides a reduction of ADHD symptoms following the
training, a pronounced increase of the CNV amplitude
was observed in CPT cue trials The authors suggested
that the CNV increase may be interpreted as a
neuro-physiological correlate of improved self-regulatory
capabil-ities Expecting a relevant stimulus, children with ADHD
may be able to allocate more resources after neurofeedback
Interestingly, similar effects on the CNV were reported
fol-lowing cognitive-behavioral interventions Against that
background future neurofeedback studies may directly aim
at the modulation of CNV and explicitly address impaired
preparatory processes and timing as an important target of
treatment [64]
Competing interests
This work is funded by the German Research Foundation (DFG; ref: HO 2503/
4-1; HO 2503/4-2).
MH has served in an advisory or consultancy role for: Lilly, Novartis, and
Bristol-Myers Squibb, and has received conference attendance support or
was paid for public speaking by AstraZeneca, Janssen-Cilag, Lilly, Neuroconn,
Novartis, Medice, and Shire BP was paid for public speaking by Lilly and
Novartis US was paid for public speaking by Novartis, Medice, Neuroconn,
the German Society for Biofeedback and Akademie König und Müller The
present work is unrelated to the above grants and relationships The other
authors have no conflicts of interest.
Authors ’ contributions
MH and US conceived the research project; they designed the study; and
together with SW and DW designed and tailored the study protocol All
authors contributed to the writing of the manuscript All authors read and
approved the final manuscript.
Authors ’ information Ute Strehl Senior author.
Author details
1 Hospital for Child and Adolescent Psychiatry, LWL University Hospital Hamm
of the Ruhr-University Bochum, Heithofer Allee 64, 59071 Hamm, Germany.
2 Interdisciplinary Centre for Clinical Trials (German abb.: IZKS), University Medical Centre Mainz, Langenbeckstr 255131 Mainz, Germany.3Institute of Medical Psychology and Behavioral Neurobiology, Eberhard-Karls-University Tübingen, Silcherstr 5, 72076 Tübingen, Germany.
Received: 26 June 2014 Accepted: 7 August 2014 Published: 13 August 2014
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